Abstract A085: OBP-004, a novel small-molecule dual inhibitor of CDK9/13, reduces bone, brain, lung and lymph node metastases in vivo, with highest potency on bone metastases
Notice bibliographique
Résumé
Abstract Cyclin-dependent kinases (CDKs) are promising targets in metastatic cancers. OBP-004 is a novel highly potent and selective small-molecule dual inhibitor of CDK9/13. It has a half-life of 17-20 hours and high tissue biodistribution in brain, lung, spleen and kidneys, and with no observed safety issues. Metastases are the main cause of cancer-related deaths. Advanced stage triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) patients have a high incidence of bone metastases that are mostly unresponsive to current treatments. In this study, we demonstrate preclinical efficacy of OBP-004 on metastatic tumor burden, and more specifically on TNBC and CRPC bone metastases using sophisticated preclinical models. For studying efficacy on multiple metastases, female NMRI nude mice were inoculated intravenously with luciferase-labelled MV4-11 human acute myeloid leukemia cells and randomized to treatment groups at day 15 based on body weight and bioluminescence imaging (BLI) signal. OBP-004 was given orally at a dose of 1.0 mg/kg three times a week (3-day on, 4-day off) starting at day 15 after the cancer cell inoculation. Tumor burden was monitored by BLI and the study was terminated at day 32. To model bone metastases in vivo, female BALB/c or castrated male C57BL mice were inoculated intratibially with luciferase-labelled 4T1 mouse TNBC or RM-1 mouse CRPC cells, respectively, and randomized to treatment groups at day 4 based on body weight and BLI signal. OBP-004 was given orally starting at day 4 after the cancer cell inoculation at a dose of 0.8 mg/kg three times a week (Mon/Wed/Fri) in the TNBC model and 0.6 mg/kg daily in the CRPC model. The TNBC study was terminated at day 21, and the CRPC study at day 28 after the cancer cell inoculation. During the study, tumor growth was monitored by BLI, cancer-induced bone changes by X-ray radiography, and bone pain by mechanical allodynia using Von Frey filaments. The initial 1.0 mg/kg dosing (3-day on, 4-day off) of OBP-004 in the MV4-11 study resulted in slight decrease of body weight without any clinical signs. The optimized dosing schedules, either with 0.8 mg/kg (Mon/Wed/Fri) or 0.6 mg/kg daily in the TNBC and CRPC studies, was well tolerated with no changes in body weight. In the MV4-11 model, OBP-004 showed strong decrease of brain, lung and lymph node metastases, and almost complete (>99.9%) abolishment of bone metastases. In both the TNBC and CRPC models, OBP-004 showed strong inhibition of tumor growth in bone, decreased cancer-induced bone loss and decreased bone pain. We conclude that OBP-004, a highly potent and selective dual inhibitor of CDK9/CDK13, is a promising preclinical drug candidate especially for the treatment of bone metastatic TNBC and CRPC. These results indicate that OBP-004 affects both tumor growth and cancer-induced bone changes, and the observed decrease in bone pain indicates potential for increasing the quality of life of bone metastatic patients. Citation Format: Tiina E. Kähkönen, Gergana Galabova, Jie Wen, Ru Yang, Michael Thormann, Jussi Halleen. OBP-004, a novel small-molecule dual inhibitor of CDK9/13, reduces bone, brain, lung and lymph node metastases in vivo, with highest potency on bone metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A085.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».